title: IL-4 induces differentiation of human embryonic stem cells into fibrogenic fibroblast-like cells.
abstract: BACKGROUND
  Fibroblast heterogeneity is recognized, and fibroblasts from diseased tissues, including those of asthmatic subjects, have functional phenotypes that differ from normal tissue. However, progenitor-progeny relationships and the factors that control fibroblast differentiation are poorly defined.
  
  
  OBJECTIVE
  We sought to determine whether IL-4 could alter the functional phenotype of fibroblasts during their differentiation from stem/progenitor cells.
  
  
  METHODS
  Using a 3-dimensional collagen gel system, we obtained embryoid bodies derived from human embryonic stem cells and recovered spindle-shaped cells consistent with fibroblasts that had differentiated in the presence or absence of IL-4.
  
  
  RESULTS
  IL-4-induced fibroblast-like cells were more active in contraction of collagen gels, migration, and production of fibronectin than control (without IL-4) cells. IL-4-induced cells demonstrated less expression of miR-155, which modulated contraction, migration, and fibronectin production. These differences persisted in culture without further addition of IL-4, suggesting the differentiated phenotype might be a permanent alteration.
  
  
  CONCLUSIONS
  The current study demonstrates that IL-4 induces differentiation of stem/precursor cells into fibroblast-like cells that demonstrate a more fibrogenic phenotype, which is due to reduced expression of miR-155. These findings provide a novel mechanism for the persistent abnormalities in IL-4-related diseases and a novel target to regulate tissue remodeling by fibroblasts.
authors.affiliation: Department of Internal Medicine, Pulmonary, Critical Care, Sleep and Allergy Medicine, University of Nebraska Medical Center, Omaha, NE 68198-5910, USA.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Sato
authors.forename: Xiangde
authors.initials: X
authors.lastname: Liu
authors.forename: Hesham
authors.initials: H
authors.lastname: Basma
authors.forename: Shinsaku
authors.initials: S
authors.lastname: Togo
authors.forename: Hisatoshi
authors.initials: H
authors.lastname: Sugiura
authors.forename: Amy
authors.initials: A
authors.lastname: Nelson
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakanishi
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Kanaji
authors.forename: Xingqi
authors.initials: X
authors.lastname: Wang
authors.forename: Miok
authors.initials: M
authors.lastname: Kim
authors.forename: Yingji
authors.initials: Y
authors.lastname: Li
authors.forename: Joel
authors.initials: J
authors.lastname: Michalski
authors.forename: Maha
authors.initials: M
authors.lastname: Farid
authors.forename: John G
authors.initials: JG
authors.lastname: Sharp
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Rennard
mesh_terms: D000199:Actins / Q000378:metabolism; D018929:Cell Culture Techniques; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D019070:Cell Lineage; D003094:Collagen; D058732:Embryoid Bodies / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D005782:Gels; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology*; D035683:MicroRNAs / Q000235:genetics; D010641:Phenotype; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D005782:Gels; C508598:IL4 protein, human; C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D011994:Recombinant Proteins; D015847:Interleukin-4; D003094:Collagen